Impairment of Body Growth in Mucopolysaccharidoses

  • Shunji Tomatsu
  • Adriana M. Montaño
  • Hirotaka Oikawa
  • Roberto Giugliani
  • Paul Harmatz
  • Mary Smith
  • Yasuyuki Suzuki
  • Tadao Orii


Children with mucopolysaccharidoses (MPS) grow poorly and become physically handicapped because of systemic bone disease. For children with skeletal dysplasias, such as MPS, it is important to know the natural history of growth. Understanding of the growth pattern provides assessment of current growth and data on efficacy of individualized medicine in growth-promoting treatments. The purpose of this chapter is to review natural history of growth patterns for MPS II, IVA, and VI patients. The cross-sectional and/or longitudinal data were collected to develop growth curves for the following types of MPS. Interestingly, accelerated growth has been observed in the first years of life in any type of MPS reviewed here, followed by slowing growth rate and growth failure. (1) MPS II: We obtained height and weight measurements from 46 Japanese male patients with MPS II. Mean birth length of boys was 50.9 ± 2.1 cm. The mean height for MPS II at 18 years of age or older was 127.2 ± 8.5 cm. These values corresponded to 0.9 SD and −7.5 SD of the height for normal Japanese males. The mean height was kept higher until 5 years and the mean weight was heavier until 8 years of age. After 7 years of age, short stature was commonly observed in spite of clinical severity by CNS involvement. (2) MPS IVA: Height and weight measurements from 193 girls and 195 boys with MPS IVA were collected. Mean birth lengths of boys and girls were 52.4 ± 3.9 and 52.1 ± 2.9 cm, respectively. Mean heights for males and females at 18 years of age were 119.3 ± 22.6 and 113.5 ± 23.1 cm, respectively. These values correspond to −8.0 SD and −7.7 SD of the mean height for normal males and females. Mean birth weights for boys and girls were 3.56 ± 0.5 and 3.5 ± 0.7 kg, respectively. (3) MPS VI: Growth is severely impacted on this type of MPS. In an observational study in 121 untreated MPS VI patients, a mean height was 115.2 cm ± 26.1 cm and median height was 103.7 cm with a range of 80–169 cm. An inverted correlation of height with the excretion of urinary GAGs and an influence of the genotype on the pattern of this excretion were also demonstrated. Thus, the growth pattern in MPS II patients was characterized by impaired growth velocity after 4 years of age, while the growth patterns in MPS IVA and VI patients were characterized by impaired growth velocity after 1 and 2 years of age.


Short Stature Carpal Tunnel Syndrome Enzyme Replacement Therapy Final Height Hematopoietic Cell Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Body mass index


Centers for Disease Control and Prevention


Chondroitin sulfate


Dermatan sulfate


Enzyme replacement therapy




N-Acetylgalactosamine-6-sulfate sulfatase


Growth hormone


Hematopoietic cell transplantation


Heparan sulfate


Insulin-like growth factor-1




Keratan sulfate





This study was supported by grants from Ariana’s Cure Fund for Morquio, the Austrian Research Society for Mucopolysaccharidoses and Related Diseases, Bennett Foundation, Care for Carly Foundation, Care for Sota Morquio Foundation, German MPS Society, International Morquio Organization (Carol Ann Foundation), Italian MPS Society, Jacob Randall Foundation, Miracle for Eddie Foundation, National MPS Society, Muconetwork, and Spanish MPS Society. The MPS VI clinical trials were sponsored by BioMarin Pharmaceutical Inc., and supported, in part, with funds provided by the National Center for Research Resources, 5 M01 RR-01271 (Dr. Harmatz). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Conflict of Interest: Dr. Harmatz, has provided consulting support to Shire HGT and BioMarin Pharmaceutical Inc. Dr. Harmatz also report receiving a speaker’s honorarium and travel support from BioMarin, Shire and Genzyme.


  1. Abreu S, Hayden J, Berthold P, Shapiro IM, Decker S, Patterson D, Haskins M. Growth plate pathology in feline mucopolysaccharidosis VI. Calcif Tissue Int. 1995;57:185–90.PubMedCrossRefGoogle Scholar
  2. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia. Pediatrics. 2000;105:e10.PubMedCrossRefGoogle Scholar
  3. Ayatollahi SM, Pourahmad S. Height and weight of primary schoolchildren in Shiraz city, southern Iran, 2002. Am J Hum Biol. 2006;18:838–40.PubMedCrossRefGoogle Scholar
  4. Azevedo ACM, Schwartz IV, Kalakun L, Brustolin S, Burin MG, Beheregaray APC, Leistner S, Giugliani C, Rosa M, Barrios P, Marinho D, Esteves P, Valadares E, Boy R, Horovitz D, Mabe P, da Silva LCS, de Souza ICN, Ribeiro M, Martins AM, Palhares D, Kim CA, Giugliani R. Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI. Clin Genet. 2004;66:208–13.PubMedCrossRefGoogle Scholar
  5. Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, Kohlschütter A, Kampmann C, Beck M. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28:1011–7.PubMedCrossRefGoogle Scholar
  6. Beck M, Glössl J, Grubisic A, Spranger J. Heterogeneity of Morquio disease. Clin Genet. 1986;29:325–31.PubMedCrossRefGoogle Scholar
  7. Butler MG, Meany FJ. An anthropometric study of 38 individuals with Prader–Labhart–Willi syndrome. Am J Hum Genet. 1987;26:445–55.Google Scholar
  8. Byers S, Nuttall, Crawley AC, Hopwood JJ, Smith K, Fazzalari NL. Effect of enzyme replacement therapy on bone formation in a feline model of mucopolysaccharidosis type VI. Bone. 1997;21:425–31.PubMedCrossRefGoogle Scholar
  9. Clementi M, Milani S, Mammi I, Boni S, Monciotti C, Tenconi R. Neurofibromatosis type 1 growth charts. Am J Med Genet. 1999;87:317–23.PubMedCrossRefGoogle Scholar
  10. Cole TJ, Green PJ. Smoothing reference centile curves: The LMS method and penalized likelihood. Stat Med. 1992;11:1305–19.PubMedCrossRefGoogle Scholar
  11. Cole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med. 1998;17:407–29.PubMedCrossRefGoogle Scholar
  12. Decker C, Yu ZF, Giugliani R, Schwartz IV, Guffon N, Teles EL, Miranda MC, Wraith JE, Beck M, Arash L, Scarpa M, Ketteridge D, Hopwood JJ, Plecko B, Steiner R, Whitley CB, Kaplan P, Swiedler SJ, Conrad S, Harmatz P. Enzyme replacement therapy for mucopolysaccharidosis VI: Growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase. J Pediatr Rehabil Med. 2010;3(2):89–100.PubMedGoogle Scholar
  13. Erkula G, Jones KB, Sponseller PD, Dietz HC, Pyeritz RE. Growth and maturation in Marfan syndrome. Am J Med Genet. 2002;109:100–15.PubMedCrossRefGoogle Scholar
  14. Gawlik A, Gawlik T, Augustyn M, Woska W, Malecka-Tendera E. Validation of growth charts for girls with Turner syndrome. Int J Clin Pract. 2006;60:150–5.PubMedCrossRefGoogle Scholar
  15. Giugliani R, Harmatz P, Wraith JE. Management guidelines for mucopolysaccharidosis VI. Pediatrics. 2007;120:405–18.PubMedCrossRefGoogle Scholar
  16. Gollust SE, Thompson RE, Gooding HC, Biesecker BB. Living with achondroplasia in an average-sized world: an assessment of quality of life. Am J Med Genet A. 2003;120A:447–58.PubMedCrossRefGoogle Scholar
  17. Harmatz P, Whitley CB, Waber L, Pais R, Steiner R, Plecko B, Kaplan P, Simon J, Butensky E, Hopwood JJ. Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux–Lamy syndrome). J Pediatr. 2004;144:574–80.PubMedCrossRefGoogle Scholar
  18. Harmatz P, Ketteridge D, Giugliani R, Guffon N, Teles EL, Miranda MC, Yu ZF, Swiedler SJ, Hopwood JJ. Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux–Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase. Pediatrics. 2005;115:e681–9.PubMedCrossRefGoogle Scholar
  19. Harmatz P, Giugliani R, Schwartz I, Guffon N, Teles EL, Miranda MC, Wraith JE, Beck M, Arash L, Scarpa M, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J Pediatr. 2006;148:533–9.PubMedCrossRefGoogle Scholar
  20. Harmatz P, Giugliani R, Schwartz IV, Guffon N, Teles EL, Miranda MC, Wraith JE, Beck M, Arash L, Scarpa M, et al. Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase. Mol Genet Metab. 2008;94:469–75.PubMedCrossRefGoogle Scholar
  21. Hauffa BP, Schlippe G, Roos M, Gillessen-Kaesbach G, Gasser T. Spontaneous growth in German children and adolescents with genetically confirmed Prader–Willi syndrome. Acta Paediatr. 2000;89:1302–11.PubMedCrossRefGoogle Scholar
  22. Heron D, Baumann C, Benichou JJ, Harpey JP, Le Merrer M. Early diagnosis of Maroteaux–Lamy syndrome in two patients with accelerated growth and advanced bone maturation. Eur J Pediatr. 2004;163:323–6.PubMedCrossRefGoogle Scholar
  23. Herskhovitz E, Young E, Rainer J, Hall CM, Lidchi V, Chong K, Vellodi A. Bone marrow transplantation for Maroteaux–Lamy syndrome (MPS VI): Long-term follow-up. J Inherit Medab Dis. 1999;22:50–62.CrossRefGoogle Scholar
  24. Hoover-Fong JE, Schulze KJ, McGready J, Barnes H, Scott CI. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr. 2008;88:364–71.PubMedGoogle Scholar
  25. Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, Izykowski B, Phillips J, Doroshow R, Walot I, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001;344:182–8.PubMedCrossRefGoogle Scholar
  26. Kanazawa T, Yasunaga Y, Ikuta Y, Harada A, Kusaka O, Sukegawa K. Femoral head dysplasia in Morquio disease type A: Bilateral varus osteotomy of the femur. Acta Orthop Scand. 2001;72:18–21.PubMedCrossRefGoogle Scholar
  27. Karageorgos L, Brooks DA, Pollard A, Melville EL, Hein LK, Clements PR, Ketteridge D, Swiedler SJ, Beck M, Giugliani R, Harmatz P, Wraith JE, Guffon N, Teles EL, Miranda MCS, Hopwood JJ. Mutational analysis of 105 mucopolysaccharidosis type VI patients. Hum Mutat. 2007;28:897–903.PubMedCrossRefGoogle Scholar
  28. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC growth charts for the United States: methods and development. Vital Health Stat. 2002;11:1–190.Google Scholar
  29. Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet. 1990;85:389–90.PubMedCrossRefGoogle Scholar
  30. Marinescu RC, Mainardi PC, Collins MR, Kouahou M, Coucourde G, Pastore G, Eaton-Evans J, Overhauser J. Growth charts for cri-du-chat syndrome: an international collaborative study. Am J Med Genet. 2000;94:153–62.PubMedCrossRefGoogle Scholar
  31. Martin NDT, Smith WR, Cole TJ, Preece MA. New height, weight and head circumference charts for British children with Williams syndrome. Arch Dis Child. 2007;97:598–601.CrossRefGoogle Scholar
  32. Martin R, Beck M, Eng C, Giugliani R, Harmatz P, Muñoz V, Muenzer J. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121:e377–86.PubMedCrossRefGoogle Scholar
  33. McGill JJ, Inwood AC, Coman DJ, Lipke ML, Skinner J, Morris B, Adsett D, Nevin N, Smith H, Hopwood JJ, Swiedler S. Enzyme replacement therapy for MPS VI with recombinant human N-acetylgalactosamine 4-sulphatase (rhASB) from 8 weeks of age – a sibling control study. J Inherit Met Dis. 2006;29(Suppl 1):65.Google Scholar
  34. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54.PubMedCrossRefGoogle Scholar
  35. Monroy MA, Ross FP, Teitelbaum SL, Sands MS. Abnormal osteoclast morphology and bone remodeling in a murine model of a lysosomal storage disease. Bone. 2002;30:352–9.PubMedCrossRefGoogle Scholar
  36. Montaño AM, Sukegawa K, Kato Z, Carrozzo R, Di Natale P, Christensen E, Orii KO, Orii T, Kondo N, Tomatsu S. Effect of ‘attenuated’ mutations in mucopolysaccharidosis IVA on molecular phenotypes of N-acetylgalactosamine-6-sulfate sulfatase. J Inherit Metab Dis. 2007a;30:758–67.PubMedCrossRefGoogle Scholar
  37. Montaño AM, Tomatsu S, Brusius A, Smith M, Orii T. Growth charts for patients affected with Morquio A disease. Am J Med Genet A. 2008;146A(10):1286–95.PubMedCrossRefGoogle Scholar
  38. Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007b;30:165–74.PubMedCrossRefGoogle Scholar
  39. Muenzer J, Lamsa JC, Garcia A, Dacosta J, Garcia J, Treco DA. Enzyme replacement therapy in mucopolysaccharidosis type II (Hunter syndrome): a preliminary report. Acta Paediatr Suppl. 2002;91:98–9.PubMedCrossRefGoogle Scholar
  40. Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006;8:465–73.PubMedCrossRefGoogle Scholar
  41. Myrelid A, Gustafsson J, Ollars B, Annerén G. Growth charts for Down’s syndrome from birth to 18 years of age. Arch Dis Child. 2002;87:97–103.PubMedCrossRefGoogle Scholar
  42. Nagashima K, Endo H, Sakakibara K, Konishi Y, Miyachi K, Wey JJ, Suzuki Y, Onisawa J. Morphological and biochemical studies of a case of mucopolysaccharidosis II (Hunter’s syndrome). Acta Pathol Jpn. 1976;26:115–32.PubMedGoogle Scholar
  43. Nelson J. Incidence of mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997;101:355–8.PubMedCrossRefGoogle Scholar
  44. Neufeld E, Muenzer J. The mucopolysaccharidoses Chapter 136. In: Scriver C, editor. Metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001. Google Scholar
  45. Nuttall JD, Brumfield LK, Fazzalari NL, Hopwood JJ, Byers S. Histomorphometric analysis of the tibial growth plate in a feline model of mucopolysaccharidosis type VI. Calcif Tissue Int. 1999;65:47–52.PubMedCrossRefGoogle Scholar
  46. Nysom K, Mølgaard C, Hutchings B, Michaelsen KF. Body mass index of 0 to 45-y-old Danes: reference values and comparison with published European reference values. Int J Obes. 2001;25:177–84.CrossRefGoogle Scholar
  47. Oda H, Sasaki Y, Nakatani Y, Maesaka H, Suwa S. Hunter’s syndrome. An ultrastructural study of an autopsy case. Acta Pathol Jpn. 1988;38:1175–90.PubMedGoogle Scholar
  48. Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, Grummer-Strawn LM, Curtin LR, Roche AF, Johnson CL. Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics. 2002;109:45–60.PubMedCrossRefGoogle Scholar
  49. Ohashi A, Montaño AM, Colón JE, Oguma T, Luisiri A, Tomatsu T. Sacral dimple: Incidental findings from newborn evaluation. Acta Paediatr. 2009;98:768–9, 910–2.PubMedCrossRefGoogle Scholar
  50. Oliver H, Jameson KA, Sayer AA, Cooper C, Dennison EM. Growth in early life predicts bone strength in late adulthood: the Hertfordshire Cohort Study. Bone. 2007;41:400–405.PubMedCrossRefGoogle Scholar
  51. Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, Pinto E, Silva E, Rocha S, Marcão A, Ribeiro I, Lacerda L, Ribeiro G, Amaral O, Sá Miranda MC. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004;12:87–92.PubMedCrossRefGoogle Scholar
  52. Polgreen LE, Tolar J, Plog M, Himes JH, Orchard PJ, Whitley CB, Miller BS, Petryk A. Growth and endocrine function in patients with Hurler syndrome after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008;41:1005–11.PubMedCrossRefGoogle Scholar
  53. Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, Niezen-Koning KE, van Diggelen OP. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999;105:151–6.PubMedGoogle Scholar
  54. Ross JL, Sandberg DE, Rose SR, Leschek EW, Baron J, Chipman JJ, Cassorla FG, Quigley CA, Crowe BJ, Roberts K, Cutler GB Jr. Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. J Clin Endocrinol Metab. 2004;89:4873–8.PubMedCrossRefGoogle Scholar
  55. Russell C, Hendson G, Jevon G, Matlock T, Yu J, Aklujkar M, Ng KY, Clarke LA. Murine MPS I: insights into the pathogenesis of Hurler syndrome. Clin Genet. 1998;53:349–61.PubMedCrossRefGoogle Scholar
  56. Schwartz IV, Ribeiro MG, Mota JG, Toralles MB, Correia P, Horovitz D, Santos ES, Monlleo IL, Fett-Conte AC, Sobrinho RP, Norato DY, Paula AC, Kim CA, Duarte AR, Boy R, Valadares E, De Michelena M, Mabe P, Martinhago CD, Pina-Neto JM, Kok F, Leistner-Segal S, Burin MG, Giugliani R. A clinical study of 77 patients with mucopolysaccharidosis type II. Acta Paediatr Suppl. 2007;96:63–70.PubMedCrossRefGoogle Scholar
  57. Silveri CP, Kaplan FS, Fallon MD, Bayever E, August CS. Hurler syndrome with special reference to histologic abnormalities of the growth plate. Clin Orthop Relat Res. 1991;269:305–11.PubMedGoogle Scholar
  58. Simonaro CM, Haskins ME, Schuchman EH. Articular chondrocytes from animals with a dermatan sulfate storage disease undergo a high rate of apoptosis and release nitric oxide and inflammatory cytokines: a possible mechanism underlying degenerative joint disease in the mucopolysaccharidoses. Lab Invest. 2001;81:1319–28.PubMedCrossRefGoogle Scholar
  59. Simonaro CM, D’Angelo M, Haskins ME, Schuchman EH. Joint and bone disease in mucopolysaccharidoses VI and VII: identification of new therapeutic targets and biomarkers using animal models. Pediatr Res. 2005;57(5 Pt 1):701–7.PubMedCrossRefGoogle Scholar
  60. Simonaro CM, D’Angelo M, He X, Eliyahu E, Shtraizent N, Haskins ME, Schuchman EH. Mechanism of glycosaminoglycan-mediated bone and joint disease: implications for the mucopolysaccharidoses and other connective tissue diseases. Am J Pathol. 2008;172:112–22.PubMedCrossRefGoogle Scholar
  61. Soper BW, Pung AW, Vogler CA, Grubb JH, Sly WS, Barker JE. Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not prevent postnatal losses. Pediatr Res. 1999;45:180–6.PubMedCrossRefGoogle Scholar
  62. Suzuki Y, Aoyama A, Kato T, Shimozawa N, Orii T. Retinitis pigmentosa and mucopolysaccharidosis type II: an extremely attenuated phenotype. J Inherit Metab Dis. 2009;32:582–3.PubMedCrossRefGoogle Scholar
  63. Toledo SP, Costa VH, Fukui RR, Abelin N. Serum growth hormone levels in Hunter’s syndrome. Rev Hosp Clin Fac Med Sao Paulo. 1991;46:9–13.PubMedGoogle Scholar
  64. Witt DR, Keena BA, Hall JG, Allanson JE. Growth curves for height in Noonan syndrome. Clin Genet. 1986;30:150–3.PubMedCrossRefGoogle Scholar
  65. Zimet GD, Owens R, Dahms W, Cutler M, Litvene M, Cuttler L. Psychosocial outcome of children evaluated for short stature. Arch Pediatr Adolesc Med. 1997;151:1017–23.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Shunji Tomatsu
    • 1
  • Adriana M. Montaño
    • 1
  • Hirotaka Oikawa
    • 1
  • Roberto Giugliani
    • 2
  • Paul Harmatz
    • 3
  • Mary Smith
    • 4
  • Yasuyuki Suzuki
    • 5
  • Tadao Orii
    • 5
  1. 1.Department of PediatricsSaint Louis UniversitySt. LouisUSA
  2. 2.Medical Genetics Service/HCPAPorto AlegreBrazil
  3. 3.Children’s Hospital & Research Center OaklandOaklandUSA
  4. 4.International Morquio OrganizationPhoenixUSA
  5. 5.Department of PediatricsGifu University School of MedicineGifuJapan

Personalised recommendations